Currently only three types of drugs (except that corticosteroids, which have anti-inflammatory effects): agonists of beta-adrenergic receptors (rapid and prolonged action); cholinolytics (muscarinic receptor antagonists); Theophylline (a derivative of purine) are used in therapy of asthma and other bronchial obstructive diseases.
In addition, the therapy schema is now included the regular use of inhaled corticosteroids alone or in combination with long-acting beta-agonists. However, despite such seemingly effective remedies, about half of patients with asthma is poorly responding to the therapy. Another problem is acute attacks of asphyxia. The ability of these drugs to stop the asthma attack for patients with a long history of the use of long acting beta-agonists is diminished. One of the solution the problem of expansion of the arsenal of broncholytic drugs is to exploit an alternative pharmacological targets.
Known is the bronchial dilating effect of natural prostaglandin E2, mediated by its interaction with the second sub-type EP-receptors (X. Norel, L. Walch, C. Labat, J-P. Gascard, E. Dulmet, C. Brink. Prostanoid receptors involved in the relaxation of human bronchial preparations.//British Journal of Pharmacology (1999) 126, 867-872), which is observed as in experiments in vitro on isolated strips of bronchus, as in vivo experiments on laboratory animals. However, the use of natural prostaglandin E2 to cut off bronchoconstriction in individuals is not possible because of the strong cough reflex.
The task of elimination of this side effect has been solved by the authors of this invention by modification of molecules of prostaglandin by introducing an additional fragment containing the nitro group, namely by obtaining 1′,3′-dinitroglycerol ester of 11(S),15(S)-dihydroxy-9-keto-5Z,13E-prostadienoic acid—derivative of natural prostaglandin E2, named nitroproston. How to prepare nitroproston and spectrum of its activity in the smooth muscle experiments have been described by the authors of this invention in the earlier patent of RU 2067094. In experiments on relaxation of the guinea pig trachea a value EC50 0.007±0.025 mkM for nitroproston vs 0.14±0.08 mkM—for natural prostaglandin E2 was obtained, demonstrating considerably more significant activity of nitroproston compared to the natural prostaglandin. However, as with natural prostaglandin E2, the data collected on the smooth muscle of experimental animals, did not permits to make a conclusion on the suitability of the substance as a bronchial dilating drug for the application in humans. The authors conducted additional research on healthy volunteers and patients with bronchial asthma, to demonstrate the effectiveness of application of nitroproston as a broncholytics in humans, that does not cause noticeable side effects.